This investigation has two broad and long range objectives. Our first goal is to establish the clinical feasibility of integrating a novel anti-angiogenesis agent, bevacizumab, into a contemporary treatment program of chemotherapy, radiation therapy, and surgery for patients with primary and non-metastatic rectal carcinoma. Our second objective is to clarify through correlative studies the mechanisms by which bevacizumab inhibits angiogenesis in concert with other therapeutic modalities in the treatment of this malignancy. Bevacizumab is a recombinant, humanized antibody to vascular endothelial growth factor (VEGF), which is overexpressed in rectal cancer and is associated with disease progression and inferior survival. Importantly, this data may aid further development of this novel agent in the treatment of rectal cancer. The central hypothesis of this proposal is that inhibition of VEGF will result in clinical benefit through enhancement of radiation and chemotherapy response for patients with rectal cancer. We will address this hypothesis using two specific aims: AIM 1: A phase I clinical trial will be undertaken to establish the maximum tolerable dose (MTD) of bevacizumab when combined with chemotherapy, radiation therapy, and surgery. Following this determination, an additional cohort of 20 patients will be treated to further assess tolerance and efficacy of this treatment program. AIM 2: To evaluate the mechanisms of effect of this therapy on rectal cancer, angiogenesis assays will be carried out using rectal cancer biopsy samples, blood, urinary samples, interstitial tumor pressure measurements, and radiological imaging (perfusion CT scans and PET scans). These assays will be performed before, during, and after treatment.